Cytochrome oxidase, the terminal respiratory complex of mitochondria, consists of seven subunit polypeptides of which three have been shown to be synthesized in mitochondria and four on cytoplasmic ribosomes. Both nuclear and mitochondrial mutants with specific lesions in cytochrome oxidase have been isolated. The mitochondrial mutants fall into three distinct genetic loci,all localized on mitochondrial DNA. Two of the loci map between the drug resistance markers PAR 1 and RIB 1. The third locus represents a very long stretch of mitochondrial DNA that lies between the resistance markers PAR 1 and OLI 2. These studies establish a dual biosynthetic and genetic derivation of cytochrome oxidase.